Fluorinated bile acids

Abstract

Compounds of general formula (1): wherein R 1 , R 2 and R 3 are as defined herein; are of use in the treatment and prevention of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease.

1 . A compound of general formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         one of R 1  and R 2  is F, and the other of R 1  and R 2  is H or F; 
         Y is selected from a bond, and a C 1-20  alkylene, C 2-20  alkenylene or C 2-20  alkynylene linker group; 
         R 3  is selected from C(O)OR 12 , C(O)NR 12 R 13 , S(O) 2 R 12 , OS(O) 2 R 12 , S(O) 2 OR 12 , OS(O) 2 OR 12 , S(O) 2 NR 12 R 13 , C(O)NR 12 S(O) 2 R 13 , NHC(O)NR 12 S(O) 2 R 13 , OP(O)(OR 12 ) 2 , C(O)NR 12 [CH(R 15 )] n R 16  and C(O)NR 12 C(O)CH 2 NR 12 [CH(R 15 )] n R 16 ;
 each R 12  is independently selected from H and C 1-6  alkyl optionally substituted by one or more substituents selected from halo, OR 10 , NR 10 R 11 , R 16  and aryl;
 each R 10  and R 11  is independently selected from H and C 1-6  alkyl; 
 
 R 13  is H, C 1-6  alkyl optionally substituted by one or more substituents selected from halo and aryl; or a 3- to 8-membered carbocyclic ring or heterocyclic ring, wherein said carbocyclic or heterocyclic ring is optionally substituted with one or more substituents selected from ═O and R 16 ; or a phenyl or 5- or 6-membered heteroaryl ring, wherein said phenyl or heteroaryl ring is optionally substituted with a substituent R 16 ; or 
 when R 3  is C(O)NR 12 R 13  or S(O) 2 NR 12 R 13 , R 12  and R 13  together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclic ring which optionally contains one or more further hetero atoms selected from N, O and S; and is optionally substituted with one or more substituents selected from CH 2 C(O)OH, C(O)OH, C 1-6  alkyl, C(O)OC 1-6  alkyl, S(O) 2 OH, ═O and ═N—OH; and is optionally fused to a phenyl group unsubstituted or substituted with one or more substituents selected from halo and nitro; 
 n is 1, 2 or 3; 
 each R 15  is independently selected from H and C 1-6  alkyl optionally substituted by one or more substituents selected from halo, phenyl and 5- or 6-membered heteroaryl; a 3- to 8-membered cycloalkyl group; or a group R 14 , where R 14  is a side chain of an amino acid; or 
 when n is 2 or 3, two R 15  groups together with the carbon atoms to which they are attached, and optionally an intervening carbon atom where present, can combine to form —(CH 2 ) p — such that the group [CH(R 15 )]n is a 3- to 8 membered carbocyclic ring; 
 p is 1, 2, 3, 4, 5 or 6; 
 R 16  is selected from C(O)OH, S(O) 2 OH, S(O) 2 (C 1-6  alkyl), OS(O) 2 OH and P(O)(OH) 2 ; 
 
         or a pharmaceutically acceptable salt or isotopic variant thereof. 
       
     
     
         2 . (canceled) 
     
     
         3 . A compound according to  claim 1  which is a compound of general formula (IA), (IB), (IC) or (ID): 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , Y and R 3  are as defined above for general formula (I). 
       
     
     
         4 . A compound according to  claim 3  which is a compound of general formula (IA). 
     
     
         5 . A compound according to  claim 3  which is a compound of general formula (IB). 
     
     
         6 . A compound according to  claim 1 , wherein both R 1  and R 2  are F. 
     
     
         7 . (canceled) 
     
     
         8 . A compound according to  claim 1 , wherein Y is —CH 2 CH 2 —. 
     
     
         9 . (canceled) 
     
     
         10 . A compound according to  claim 1 , wherein
 R 12  is selected from H methyl, and ethyl, and is optionally substituted with R 16  or N(R 10 )(R 11 ); or   R 3  is selected from C(O)NR 12 S(O) 2 R 13 , NHC(O)NR 12 S(O) 2 R 13 , C(O)NR 12 [CH(R 15 )] n R 16 , and C(O)NR 12 C(O)CH 2 NR 12 [CH(R 15 )] n R 16 ; and R 12  is H or methyl; and/or   R 13  is a 5- or 6-membered carbocyclic ring or heterocyclic ring optionally substituted with R 16  or ═O; or R 13  is phenyl optionally substituted with R 16 ; or   R 3  is selected from C(O)NR 12 R 13  and S(O) 2 NR 12 R 13  and R 12  and R 13  together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring optionally substituted with one or more substituents selected from R 16  and ═O and optionally comprising one or more further heteroatoms selected from O, N and S; and/or   R 16  is selected from C(O)OH, S(O) 2 OH, S(O) 2 (C 1-6  alkyl), and OS(O) 2 OH; or   R 16  is selected from C(O)OH, S(O) 2 OH, OS(O) 2 OH and P(O)(OH) 2 , and the compound is in the form of a pharmaceutically acceptable salt.   
     
     
         11 - 12 . (canceled) 
     
     
         13 . A compound according to  claim 1  wherein R 3  is C(O)NR 12 [CH(R 15 )] n R 16  or a pharmaceutically acceptable salt thereof,
 wherein R 12  is H, methyl or methyl substituted with R 16 ; 
 where R 16  is C(O)OH, S(O) 2 OH, S(O) 2 (C 1-6  alkyl) or OS(O) 2 OH. 
 
     
     
         14 - 15 . (canceled) 
     
     
         16 . A compound according to  claim 1 , wherein:
 R 3  is C(O)NR 12 CH(R 14 )C(O)OH, wherein R 12  is H or methyl and R 14  is H; or   R 3  is C(O)NR 12 CH(R 15 )CH(R 15 )S(O) 2 OH, wherein R 12  is H or methyl and both R 15  moieties are H.   
     
     
         17 . (canceled) 
     
     
         18 . A compound according to  claim 1 , wherein R 3  is C(O)NR 12 R 13  or a pharmaceutically acceptable salt thereof. 
     
     
         19 - 20 . (canceled) 
     
     
         21 . A compound according to  claim 1  selected from:
 2β-fluorochenodeoxycholic acid (Compound 1); 
 2β-fluoro-3β,7α-dihydroxy-5β-cholanic acid (Compound 2); 
 2α-fluoro-3β,7α-dihydroxy-5β-cholanic acid (Compound 3); 
 2α-fluoro-3β,7β-dihydroxy-5β-cholanic acid (Compound 4); 
 2α-fluoro-3α,7α-dihydroxy-5β-cholanic acid (Compound 5); 
 2α-fluoro-3α,7β-dihydroxy-5β-cholanic acid (Compound 6); 
 2,2-difluoro-3β,7β-dihydroxy-5β-cholanic acid (Compound 7); 
 2,2-difluoro-3α,7α-dihydroxy-5β-cholanic acid (Compound 8); 
 2,2-difluoro-3α,7β-dihydroxy-5β-cholanic acid (Compound 9); 
 N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide)-ethylsulfonic acid (Compound 10); 
 N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide)-propanoic acid (Compound 11); 
 N-(methyl),N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide)-acetic acid (Compound 12); 
 N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide)-trans-2-cyclohexane carboxylic acid (Compound 13); 
 1-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl)-piperidine-3-carboxylic acid (Compound 14); 
 3-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide)-4-thiazolidine-carboxylic acid (Compound 15); 
 N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl)-morpholine (Compound 16); 
 N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide)-methylcarboxylic acid (Compound 17) 
 N-(carboxymethyl)-N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl)-2-amino acetic acid (Compound 18); 
 N-(methyl)-N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide) ethylsulfonic acid (Compound 19); 
 3-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl) amino-propanesulfonic acid (Compound 20); 
 N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide) methanesulfonic acid (Compound 21); 
 N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl)-2-aminoethyl sulfuric acid (Compound 22); 
 O-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl)-2-hydroxy ethyl sulfonic acid (Compound 23); 
 N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl) aniline-2-sulfonic acid (Compound 24); 
 N-(cyclohexyl)-N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl)-3-amino-propanesulfonic acid (Compound 25); 
 N-(cyclohexyl)-N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl)-2-amino-ethanesulfonic acid (Compound 26); 
 N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl) 2-aminoethyl methyl sulfone (Compound 27); 
 N-(ethyl)-N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl)-3-amino-tetrahydrothiophene dioxide (Compound 28); 
 N-(2-(diisopropylamino)ethyl)-N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl)-3-amino-tetrahydrothiophene dioxide (Compound 29); 
 N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl)-thiomorpholine-dioxide (Compound 30); 
 N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-oyl) 1,1-dioxidotetrahydro-2H-thiopyran-3-ylamine (Compound 31); and 
 pharmaceutically acceptable salts thereof. 
 
     
     
         22 - 23 . (canceled) 
     
     
         24 . A method for the treatment of a neurodegenerative disorder, the method comprising administering to a patient in need of such treatment an effective amount of a compound according  claim 1 . 
     
     
         25 . (canceled) 
     
     
         26 . A method according to  claim 24 , wherein the neurodegenerative disorder is Parkinson's disease, and the compound is selected from the compounds of general formula (IA) and (ID); 
       
         
           
           
               
               
           
         
         wherein one of R 1  and R 2  is F, and the other of R 1  and R 2  is H or F; 
         Y is selected from a bond, and a C 1-20  alkylene, C 2-20  alkenylene or C 2-20  alkynylene linker group; 
         R 3  is selected from C(O)OR 12 , C(O)NR 12 R 13 , S(O) 2 R 12 , OS(O) 2 R 12 , S(O) 2 OR 12 , OS(O) 2 OR 12 , S(O) 2 NR 12 R 13 , C(O)NR 12 S(O) 2 R 13 , NHC(O)NR 12 S(O) 2 R 13 , OP(O)(OR 12 ) 2 , C(O)NR 12 [CH(R 15 )] n R 16  and C(O)NR 12 C(O)CH 2 NR 12 [CH(R 15 )] n R 16 ;
 each R 12  is independently selected from H and C 1-6  alkyl optionally substituted by one or more substituents selected from halo, OR 10 , NR 10 R 11 , R 16  and aryl;
 each R 10  and R 11  is independently selected from H and C 1-6  alkyl; 
 
 R 13  is H, C 1-6  alkyl optionally substituted by one or more substituents selected from halo and aryl; or a 3- to 8-membered carbocyclic ring or heterocyclic ring, wherein said carbocyclic or heterocyclic ring is optionally substituted with one or more substituents selected from ═O and R 16 ; or a phenyl or 5- or 6-membered heteroaryl ring, wherein said phenyl or heteroaryl ring is optionally substituted with a substituent R 16 ; or 
 when R 3  is C(O)NR 12 R 13  or S(O) 2 NR 12 R 13 , R 12  and R 13  together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclic ring which optionally contains one or more further hetero atoms selected from N, O and S; and is optionally substituted with one or more substituents selected from CH 2 C(O)OH, C(O)OH, C 1-6  alkyl, C(O)OC 1-6  alkyl, S(O) 2 OH, ═O and ═N—OH; and is optionally fused to a phenyl group unsubstituted or substituted with one or more substituents selected from halo and nitro; 
 n is 1, 2 or 3; 
 each R 15  is independently selected from H and C 1-6  alkyl optionally substituted by one or more substituents selected from halo, phenyl and 5- or 6-membered heteroaryl; a 3- to 8-membered cycloalkyl group; or a group R 14 , where R 14  is a side chain of an amino acid; or 
 when n is 2 or 3, two R 15  groups together with the carbon atoms to which they are attached, and optionally an intervening carbon atom where present, can combine to form —(CH 2 ) p — such that the group [CH(R 15 )]n is a 3- to 8 membered carbocyclic ring; 
 p is 1, 2, 3, 4, 5 or 6; and 
 R 16  is selected from C(O)OH, S(O) 2 OH, S(O) 2 (C 1-6  alkyl), OS(O) 2 OH and P(O)(OH) 2 . 
 
       
     
     
         27 . A method according to  claim 26 , wherein the compound is selected from:
 2,2-difluoro-3β,7β-dihydroxy-5β-cholanic acid (Compound 7);   difluoro-3α,7β-dihydroxy-5β-cholanic acid (Compound 9)   N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide)-ethylsulfonic acid (Compound 10);   N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide)-methylcarboxylic acid (Compound 17); and   N-(methyl)-N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide) ethylsulfonic acid (Compound 19).   
     
     
         28 . A eompound for use, a use or a method according to  claim 24 , wherein the neurodegenerative disorder is Alzheimer's disease, and wherein the compound is 2,2-difluoro-3α,7α-dihydroxy-5β-cholanic acid (Compound 8). 
     
     
         29 . (canceled) 
     
     
         30 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable excipient or carrier. 
     
     
         31 . A process for the preparation of a compound according to  claim 1 , comprising:
 A. for a compound of general formula (IB) or (IC) as defined in  claim 3  in which R 1  is F and R 3  is C(O)OR 12a : wherein R 12a  is C 1-6  alkyl optionally substituted by one or more halo or aryl groups:   treating with an acid a compound of general formula (II):   
       
         
           
           
               
               
           
         
         wherein Y and R 3  are as defined in  claim 1 ; R 12a  is C 1-6  alkyl optionally substituted by one or more halo or aryl groups; and R 21  is an OH protecting group which is acid labile; 
         B. for a compound of general formula (IA) or (IC) as defined in  claim 3  in which R 2  is F and R 3  is C(O)OR 12a , wherein R 12a  is as defined for general formula (II): 
         reducing a compound of general formula (XIIa): 
       
       
         
           
           
               
               
           
         
         wherein Y is as defined in  claim 1  and R 12a  is as defined for general formula (II); 
         C. for a compound of general formula (IB) or (ID) as defined in  claim 3  in which R 2  is F and R 3  is C(O)OR 12a , wherein R 12a  is as defined for general formula (II): 
         reducing a compound of general formula (XIIb): 
       
       
         
           
           
               
               
           
         
         wherein Y is as defined in  claim 1  and R 12a  is as defined for general formula (II); 
         D. for a compound of general formula (IA) as defined in  claim 3  in which both R 1  and R 2  are F and R 3  is C(O)OR 12a , wherein R 12a  is as defined for general formula (II): 
         reacting with an acid a compound of general formula (XXI): 
       
       
         
           
           
               
               
           
         
         wherein Y is as defined in  claim 1  and R 12a  and R 21  are as defined for general formula (II); 
         E. for a compound of general formula (IB) or (ID) as defined in  claim 3  in which both R 1  and R 2  are F and R 3  is C(O)OR 12a , wherein R 12a  is as defined for general formula (II): 
         reducing a compound of general formula (XXII): 
       
       
         
           
           
               
               
           
         
         wherein Y is as in  claim 1  and R 12a  and R 21  are as defined for general formula (II); 
         F. for a compound of general formula (I) in which R 3  is C(O)OH: 
         hydrolysing a compound of general formula (I) in which R 3  is C(O)R 12a , wherein R 12a  is as defined above for general formula (II); 
         G. for a compound of general formula (I) in which R 3  is C(O)NR 12 R 13 : 
         reacting a compound of general formula (I) in which R 3  is C(O)OH with an amine of general formula:
   H—NR 12 R 13  
 
 
         wherein R 12  and R 13  are as defined in  claim 1 ; 
         in the presence of a coupling reagent and an amine; 
         H. for a compound of general formula (I) in which R 3  is C(O)NR 12 [CH(R 15 )] n R 16 : 
         reacting a compound of general formula (I) in which R 3  is C(O)OH with a compound of general formula (XL):
   HNR 12 [CH(R 15 )] n R 16   (XL)
 
 
         wherein R 12 , R 15 , n and R 16  are as defined in  claim 1 ; 
         in the presence of a coupling agent and an amine; 
         I. for a compound of general formula (I) in which R 3  is C(O)NR 12 CH(R 14 )C(O)OH: 
         reacting a compound of general formula (I) in which R 3  is C(O)OH by reaction with an amino acid of general formula (XLI): 
       
       
         
           
           
               
               
           
         
         wherein R 12  and R 14  are as defined in  claim 1 ; 
         in the presence of a coupling agent and an amine; 
         J. for a compound of general formula (I) in which R 3  is C(O)NR 12 CH(R 15 )CH(R 15 )S(O) 2 OH: 
         reacting a compound of general formula (I) in which R 3  is C(O)OH by reaction with a compound of general formula (XLII): 
       
       
         
           
           
               
               
           
         
         wherein R 12  and R 15  are as defined in  claim 1 ; 
         in the presence of a coupling agent and an amine; 
         K. for a compound of general formula (I) in which R 3  is C(O)NR 12 S(O) 2 R 13 : 
         reacting a compound of general formula (I) in which R 3  is C(O)OH with a compound of formula:
   NHR 12 S(O) 2 R 13    
 
         wherein R 12  and R 13  are as defined in  claim 1 , in the presence of a coupling reagent and an amine; 
         L. for a compound of general formula (I) in which R 3  is NHC(O)NR 12 S(O) 2 R 13 : 
         reacting a compound of general formula (I) in which R 3  is C(O)OH as follows: 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 12  and R 13  are as defined in  claim 1 ; 
         M. for a compound of general formula (I) in which R 3  is S(O) 2 OR 12 : 
         reacting a compound of general formula (I) in which R 3  is C(O)OH with a C 1-6  alkanoyl or benzoyl chloride or with a C 1-6  alkanoic anhydride to give a protected intermediate; and 
         converting the carboxylic acid group of the protected intermediate to OH by reduction with a hydride reducing agent to give a reduced intermediate; and 
         halogenating the reduced intermediate to give a halogenated intermediate in which the OH group is replaced with a halogen; and 
         reacting the halogenated intermediate with sodium sulphite in an alcoholic solvent; 
         N. for a compound of general formula (I) in which R 3  is OS(O) 2 R 12 : 
         reacting a compound of general formula (I) in which R 3  is C(O)OR 12  with a C 1-6  alkanoyl or benzoyl chloride or with a C 1-6  alkanoic anhydride to protect any OH groups; and 
         converting the C(O)OR 12  of the protected intermediate to OH by reduction with a hydride reducing agent to give a reduced intermediate; and 
         reacting the reduced intermediate with chlorosulfonic acid in the presence of a base to give a protected product; and 
         base hydrolysis of the protected product to remove the protecting groups; or 
         O. for a compound of general formula (I) in which R 3  is S(O) 2 R 12 : 
         reacting the reduced intermediate of (M) or (N) above with Lawesson's reagent followed by oxidation of the resultant product. 
       
     
     
         32 . A compound according to  claim 1  which is 2,2-difluoro-3β,7β-dihydroxy-5β-cholanic acid (Compound 7), or a pharmaceutically acceptable salt thereof. 
     
     
         33 . A compound according to  claim 1  which is 2,2-difluoro-3α,7β-dihydroxy-5β-cholanic acid (Compound 9), or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A compound according to  claim 1  which is N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide)-ethylsulfonic acid (Compound 10), or a pharmaceutically acceptable salt thereof. 
     
     
         35 . A compound according to  claim 1  which is N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide)-methylcarboxylic acid (Compound 17), or a pharmaceutically acceptable salt thereof. 
     
     
         36 . A compound according to  claim 1  which is N-(methyl)-N-(2,2-difluoro-3β,7β-dihydroxy-5β-cholan-24-amide) ethylsulfonic acid (Compound 19), or a pharmaceutically acceptable salt thereof. 
     
     
         37 . A compound according to  claim 1  which is 2,2-difluoro-3α,7α-dihydroxy-5β-cholanic acid (Compound 8), or a pharmaceutically acceptable salt thereof.